This application addresses the broad challenge area (15) Translational Science and the specific challenge topic, 15-OD (ORDR)-101 "Pilot projects for prevention, early detection and treatment of rare diseases." Oculocutaneous albinism type 2 (OCA2) is an autosomal recessive disorder resulting from mutations in the OCA2 gene. While OCA2 is the most common form of albinism worldwide, it is a rare disorder (1in 39,000). Prevalence of OCA2 is notably higher among American minorities of African descent ( 1 in 10,000 {Witkop, 1989 #263}) and Native American descent (prevalence of 1 in 1,550-2,000 based on carrier frequency {Yi, 2003 #1520}, but reaching 1 in 200 among some Hopi groups {Woolf, 1969 #1966}). OCA2 results in hypopigmentation of the skin, hair and eyes as well as visual deficits resulting from misrouting of the optic tract and maldevelopment of the retina. In addition to loss of visual acuity, greatly increased risk of skin cancers and substantial psychosocial burdens associated with a highly visible condition also contribute to morbidity. Hypopigmentation results from the failure of melanocytes to produce melanin which protects the skin against ultraviolet radiation (UV) induced damage and reduces the risk of cutaneous cancers. Individuals with OCA2 living in areas that experience intense sunlight, such as Arizona where OCA2 is more common among the Navajo, are at greatest risk. Our laboratory has been investigating the etiology of OCA2. Consistent with the objectives of the funding program, we now aim to develop a therapeutic topical agent that will reverse cutaneous hypopigmentation in OCA2, provide improved sun protection and reduce the psychological burden of the disease. No such treatments exist currently and there are no ongoing clinical trials to address the treatment of OCA2. We have identified potential agents by screening for compounds that reverse the hypopigmentation of murine albino melanocytes in culture. In this pilot project we propose the development of a reconstructed human skin model that will provide insight into human efficacy prior to subjecting patients to an agent in clinical trials. While the ability of the "hit" compounds to induce pigmentation will be verified in mouse and human melanocytes, these experiments do not address the issue of skin penetration and metabolism by keratinocytes, which may render the compound inert or worse, produce a toxic by-product. Thus testing in a reconstructed skin model will allow for exclusion of agents that fail to promote pigmentation in a three dimensional model thereby reducing the amount of failed animal tests. In Aim 1, a reconstructed skin model will be developed that will incorporate melanocytes from either mice or human individuals with OCA2. The model will be used in Aim 2 to test the efficacy of agents identified in our recent chemical library screen by their ability to promote pigmentation in albino melanocytes. These studies will facilitate the path to clinical trials and eventual treatment of hypopigmentation in OCA2. Treatment of OCA2 will allow those who suffer from the disease to be more economically productive by decreasing the psychosocial stigma, the risk of cancers and, in the future, visual defects. Moreover, development of therapeutic agents is a significant avenue for job creation. Development and testing will require the time and effort of skilled workers in both academia and the pharmaceutical industry as will production of a marketable treatment. The utility of this model will not be limited to OCA2, but can be extended to any form of albinism or melanocyte-related disease, exponentially increasing the financial impact of the proposed research. OCA2 is a rare disorder that results hypopigmentation of the skin which causes severe psychological distress to affected individuals due to the highly visible nature of the disease and renders individuals highly susceptible to sun-induced skin cancers. In this study we aim to develop a reconstructed skin model that can be used to test the efficacy of compounds that reverse the pigment phenotype of OCA2 melanocytes in culture. Such a therapeutic agent will reverse cutaneous hypopigmentation, reduce skin cancer risk and lessen the psychosocial burden in individuals with this as yet untreatable disorder, all of which will have a positive economic impact on those who suffer from the disease while providing a new pipeline for the development of therapeutics for pigmentation disorders, which will lead to the creation of jobs in both academia and the pharmaceutical industry.